Project Summary Physical activity (PA) prevents or ameliorates a large number of diseases, and inactivity is the 4th leading global mortality risk factor. The molecular mechanisms responsible for the diverse benefits of PA are not well understood. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is being formed to advance knowledge in this area. We propose to establish PAGES, a Physical Activity Genomics, Epigenomics/transcriptomics Site as an integral component of the MoTrPAC. PAGES will conduct comprehensive analyses of the rat and human PA intervention MoTrPAC samples, contribute these data to public databases, help identify candidate molecular transducers of PA and elucidate new PA response mechanisms, and help develop predictive models of the individual response to PA. PAGES assay sites at Icahn School of Medicine at Mount Sinai, New York Genome Center and Broad Institute provide the infrastructure, expertise and experience to support this large scale, comprehensive analysis of molecular changes associated with PA. PAGES aims are to 1. Work with the MoTrPAC Steering Committee in Year 1 to finalize plans and protocols; 2. Perform assays and analyses to help Identify candidate molecular transducers of the response to PA in rat models and the pathways responsible for model differences, including high-depth RNA-seq and Whole Genome Bisulfite Sequencing (WGBS), supplemented by additional assay types such as ChIP-seq, ATAC-seq based on initial results; 3. Perform comprehensive assays and analyses of the human MoTrPAC clinical study tissue samples, including RNA-seq, WGBS, H3K27ac ChIP-seq, ATAC-seq and whole genome sequencing. 4. Collaborate with the MoTrPAC to analyze data from PAGES and other MoTrPAC analysis sites to identify candidate PA transducers and molecular mechanisms, and to develop predictive models of PA capacity and response to training. The success of PAGES and the MoTrPAC program will transform insight into the molecular networks that transduce PA into health, create an unparalleled comprehensive public PA data resource, and can provide the foundation for profound advances in the prevention and treatment of many major human diseases.